1. Field of Invention
This invention relates to .alpha.,.alpha.-disubstituted aromatic and heteroaromatic compounds, to pharmaceutical compositions containing them, processes for preparing them, and methods of using them in mammals to treat cognitive deficiencies and/or neurological dysfunction and/or mood disturbances such as found, for example, in degenerative nervous system diseases.
2. Background Including Prior Art
There is a steadily growing need for effective treatment for Nervous System Disorders causing cognitive and neurological deficiencies. Many of these diseases, of which the incidence generally rises with increasing age, are due to degenerative changes in the nervous system. Although in early stages of some diseases certain systems are rather specifically affected (e.g., cholinergic systems in Alzheimer's Disease, and Myasthenia Gravis, the dopaminergic system in Parkinson's Disease, etc.), multiple neurotransmitter system deficiencies (acetylcholine, dopamine, norepinephrine, serotonin) are generally found at later stages of diseases such as senile dementia, multi-infarct dementia, Huntington's disease, mental retardation, etc. This may explain the generally observed multiple symptomatology which includes cognitive, neurological and affective/psychotic components (see Gottfries, Psychopharmacol. 86, 245, 1985). Deficits in the synthesis and release of acetylcholine in the brain are generally thought to be related to cognitive impairment (see Francis et. al., New England J. Med., 313, 7, 1985) whereas neurological deficits (e.g., Parkinsonian symptoms) and mood/mental changes may be related to impairment of dopaminergic and serotonergic systems, respectively. Other neurological deficits (e.g., Myasthenia Gravis) are related to cholinergic deficiencies in the peripheral nervous system.
Treatment strategies employed hitherto encompass vasoactive drugs like vincamine and pentoxifylline; "metabolic enhancers" like ergoloid mesylates, piracetam and naftidrofuryl; neurotransmitter precursors like 1-DOPA, choline and 5-hydroxytryptamine; transmitter metabolizing enzyme inhibitors like physostigmine; and neuropeptides like adrenocorticotropic hormone and vasopressin-related peptides. Except for 1-DOPA treatment in Parkinson's disease and cholinesterase inhibitor treatment in Myasthenia Gravis, these treatment strategies have generally failed to produce clinically significant improvements (Hollister, Drugs, 29, 483, 1985). Another strategy to treat these multiple symptoms is to enhance the residual function of the affected systems by enhancing the stimulus-induced release of neurotransmitters. Theoretically, such an enhancement would improve the signal-to-noise ratio during chemical transmission of information, thereby reducing deficits in processes related to cognition, neurological function and mood regulation.
To date, there are not many patent or literature references which describe 3,3-heterocyclic disubstituted indolines. Most pertinent are Japanese Patent 55-129184, issued Oct. 6, 1980 and M. Ogata et. al., Eur. J. Med. Chem-Chim. Ther., 16(4), 373-378 (1981), which describe antifungal compounds having the formula: ##STR2## wherein R is H, halogen, alkyl, or alkoxy;
R.sup.1 is H, alkyl, aryl or acyl; and PA1 R.sup.2 is thienyl, or imidazole, amongst non-heterocyclic groups. PA1 R.sub.3 is H or alkyl. PA1 one of Het.sup.1 or Het.sup.2 is 2, 3, or 4-pyridyl or 2, 4, or 5-pyrimidinyl and the other is selected from PA1 Z is O or S; PA1 R is C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.8 cycloalkyl 2-pyridyl, 3-pyridyl, 4-pyridyl, or ##STR6## V, W, X, and Y independently are H, halo, C.sub.1 -C.sub.3 alkyl, OR.sup.1, NO.sub.2, CF.sub.3, CN or NR.sup.1 R.sup.2 ; PA1 R.sup.1 and R.sup.2 independently are H or C.sub.1 -C.sub.3 alkyl; PA1 Het.sup.1 and Het.sup.2 independently are 6-membered heterocyclic aromatic rings containing one or two nitrogen atoms as part of the ring optionally substituted with one substituent selected from the group C.sub.1 -C.sub.3 alkyl, halo, OR.sup.1 or NR.sup.1 R.sup.2 ; or PA1 R.sup.3 and R.sup.4 independently are H, alkyl of 1-3 carbon atoms, or acyl; PA1 B and D independently are R.sup.1 or R.sup.2 or, when A is (CH.sub.2).sub.o can be taken together to form --CH.dbd.CH--, or --CH.sub.2 --CH.sub.2 --; PA1 R.sup.5 independently is H, or is taken together with R.sup.1 to form a 2,3- or a 3,4-fused benzo ring; PA1 one of Het.sup.1 or Het.sup.2 is 2, 3, or 4-pyridyl or 2, 4 or 5-pyrimidinyl and the other is selected from: PA1 X independently when a is a double bond is CR.sup.2 or COR.sup.3 ; PA1 X and Y taken together when a is a single bond is ##STR10## X and Y taken together when a is a double bond is ##STR11## where n is 1 or 2; Q when a is a single bond is .dbd.O, .dbd.S, H.sub.2, OR.sup.3, .dbd.NOR.sup.1, ##STR12## --(H)F, F.sub.2, (R.sup.1 )OR.sup.3, .dbd.OR.sup.1 R.sup.2 ; PA1 Q when a is a double bond is R.sup.2, OR.sup.3 or halo. PA1 p is 2 or 3; PA1 R.sup.1 is H, alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, or ##STR13## R.sup.2 is R.sup.1, NO.sub.2, CN, CO.sub.2 R.sup.1, ##STR14## or halo; R.sup.3 is R.sup.1 or ##STR15## W, Y, Z independently are H, halo, alkyl of 1-3 carbon atoms, OR.sup.3, NO.sub.2, CF.sub.3, fluoroalkyl, CN, or N(R.sup.1).sub.2 ; and PA1 Her.sup.1 and Her.sup.2 are as defined in (2) above. PA1 a is a single bond or double bond; PA1 b is a single bond or double bond, provided one of a or b is a single bond; PA1 X independently when a and b are single bonds is O, S, CR.sup.1 R.sup.2, CQ, C(R.sup.1)OR.sup.3, or --(--CH.sub.2 --)--.sub.n where n is 1, 2 or 3, N(CH.sup.2).sub.p R.sup.3 where p is O or 1, or NCOR.sup.1 ; PA1 X independently when one of a or b is a double bond is CR.sup.2 , COR.sup.3 , or N; PA1 V independently when b is a single bond is CQ; PA1 V independently when b is a double bond is CR.sup.2 or COR.sup.3 ; PA1 A is a single bond, --(--CR.sub.2.sup.1 --).sub.n --, --X--, --(--CR.sub.2.sup.1 --).sub.n --X, where n is 1, 2 or 3 and PA1 X is as defined above when a is a single bond; PA1 Y and V taken together when A and b are single bond is ##STR17## Y and V taken together when A is a single bond is --CH.sub.2 --(--CH.sub.2 --).sub.m --CH.sub.2 -- where m is 1 or 2; PA1 provided that when Y and V are connected, then V and X are not connected; PA1 V and X taken together when b is a double bond is C--CH.dbd.CH--CH.dbd.CH--C--, or --C--(--CH.sub.2 --).sub.p --C; PA1 provided that when V and X are connected, then Y and V are not connected; PA1 Q when a is a single bond is .dbd.O, .dbd.S, H.sub.2, OR.sup.3, .dbd.NOR.sup.1 ##STR18## --(H)F, F.sub.2, (R.sup.1)OR.sup.3, .dbd.CR.sup.1 R.sup.2 ; Q when a is a double bond is R.sup.2, OR.sup.3 or halo; PA1 p is 2 or 3; PA1 R.sup.1 is H, alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, or ##STR19## R.sup.2 is R.sup.1, NO.sub.2, CN, CO.sub.2 R.sup.1, ##STR20## or halo; R.sup.3 is R.sup.1 or ##STR21## W, Y, Z each independently is H, halo, alkyl of 1-3 carbon atoms, OR.sup.3, NO.sub.2, CF.sub.3, CN, or N(R.sup.1 ).sub.2 ; and PA1 Het.sup.1 and Het.sup.2 are as defined in (2) above. PA1 (a) 4-pyridinyl and 4-pyridinyl, PA1 (b) 4-pyrimidinyl and 4-pyrimidinyl, PA1 (c) 4-pyridinyl and 4-pyrimidinyl, PA1 (d) 4-pyridinyl and 3-tetrahydrofuranyl. PA1 p is o; or PA1 Z is O; or PA1 X and Y are H; or PA1 R is CH.sub.3, phenyl or m-chlorophenyl; or PA1 Het.sup.1 and Het.sup.2 are each pyridyl attached by a ring carbon atom. PA1 (a) those compounds of Formula (II) where: PA1 (b) those of Formula (II) where: PA1 (c) those of Formula (II) where: PA1 (a) those of Formula (III) where: PA1 (b) those of Formula (III) where: PA1 (c) those of Formula (III) where: PA1 (a) those of Formula (IV) where: PA1 (b) those of Formula (IV) where: PA1 (c) those of Formula (IV) where: PA1 (d) those of Formula (IV) where: PA1 R.sup.3 is H or ##STR27##
R. W. Daisley, et. al.,, J. Heterocyclic Chem., 19, 1913-1916, (1982), report 1-methyl-3,3-dipiperidinoindol-2-(3H)-one as product from the reaction of the corresponding (Z) or (E) 1-arylmethylidene-indol-3 (2H) -one with ethyl cyanoacetate in the presence of excess piperidine. No utility for the compound is described.
Japanese Patent 59-98896 describes high sensitivity, high stability recording medium containing a 3,3-disubstituted-2-oxo-2,3-dihydroindole derivative of the formula shown below as a near infrared absorber. ##STR3## wherein R.sub.1, R.sub.2, same or different, are a saturated heterocyclic ring including morpholino, pyrrolidinyl, amongst others containing at least one nitrogen atom; and
3,3-bis(morpholino)oxoindole is also disclosed in U.S. Pat. No. 4,273,860, to A. Adin, Jun. 16, 1981 and in A. Adin, et. al., Research Disclosures, 184, 446-454 (1979 ), as a destabilizer material in a photoinhibitor composition utilizing cobalt (111) complexes.
The above references, other than J55-129184, and M. Ogata et. al., Eur. J. Med. Chem-Chim, Ther., 16(4), 373-378 (1981) all describe 3,3-disubstituted indolines wherein the heterocyclic groups are both saturated rings. In all of the above references, the heterocyclic ring is attached to the indoline by a ring nitrogen. Furthermore, in the references other than J55-129284, there is no suggestion of pharmaceutical utility for these 3,3-disubstituted indolines.